Methods for enhancing wound healing

ABSTRACT

A method for treating a patient having a wound is described. The method includes administering an amount of a chemodenervating agent such that healing of the wound is enhanced. The method is illustrated by detailing the mean differences of the scores of the paired experimental and control scars across three observers.

TECHNICAL FIELD

[0001] The invention relates to a method for enhancing wound healing.

BACKGROUND OF THE INVENTION

[0002] Immobilization is a basic therapeutic principle in wound healing,common to the treatment of lesions of all kinds. Casts, plates, andsutures minimize the negative effects of muscle tension on healingtissues. Since tension is one of the chief factors determining thedegree of scar formation, this principle also holds true in skinlesions. The carefully-planned execution of an elective skin incisionfrequently achieves the best aesthetic result.

[0003] Surgeons have been seeking techniques and methods to reduceexcessive scar formation, especially in the face. Many approaches havebeen undertaken to overcome the negative influence of muscular tensionon the wound healing process, including various suture techniques,steroid injections, undermining wound edges, and placing incisions in aline parallel to relaxed skin tension lines (RSTLs).

[0004] The etiology of skin tension lines, first described more than acentury ago, has been subject to controversy over the years. There isgeneral agreement, however, that skin tension lines influence thehealing of incisions according to their relative positions. There isevidence that the formation of RSTLs is a dynamic process over time.Studies on fetal calves and human fetal skin suggest that RSTLs are notgenetically determined, but represent a change of texture of the skinsecondary to extrinsic and/or intrinsic forces. Lorenz, H. P. et al.,Development, 114(1):253-259, (1992). This change in texture gives skincertain mechanical characteristics that are retained even when excised.Muscle tension is thought to be a major factor in the formation ofRSTLs.

[0005] Increased skin tension has a negative effect on wound healing,causing hypertrophic scars or wound dehiscence. See, for example,Sherris, D. A. et al., Otolaryngologic Clinics of North America,28(5):1957-1968, 1995. Repeated microtrauma, caused by continuousdisplacement of injured tissue, induces a prolonged inflammatoryresponse and an increased metabolic activity during the healing process.As a consequence, extracellular deposition of collagen andglycosaminoglycans can intensify and lead to hypertrophic scars. Theincidence of hypertrophic scars is higher in certain anatomic areaswhere there is increased muscular movement. McCarthy, J. G., PlasticSurgery, 1990, Vol. 1, Philadelphia, W B Saunders, page 44.

SUMMARY OF THE INVENTION

[0006] The invention is based, in part, on a new therapy for managementof both traumatic and iatrogenic wounds, which includes the eliminationof the tension acting on the wound. The new therapy includes injectionof a chemodenervating agent to paralyze muscles capable of exertingtension on such wounds, providing better wound healing with minimal scardevelopment. In addition, early immobilization in elective proceduresalso allows a surgeon to use finer sutures, further improving thecosmetic result.

[0007] In one aspect, the invention features a method for treating apatient having a wound (e.g., a facial wound). The method includeslocally administering an amount of a chemodenervating agent such thathealing of the wound is enhanced. The chemodenervating agent can be, forexample, a botulinum toxin, saxitoxin, tetanus toxin, or tetrodotoxin,and is typically administered by injection. The botulinum toxin can bebotulinum toxin A, B, C, D, E, F, or G, and in particular botulinumtoxin A or B. The method further can include administering an amount ofa local anesthetic agent and/or a local vasoconstrictive agent effectiveto enhance wound healing. Local anesthetic agents such as lidocaine,bupivacaine, or mepivacaine, or local vasoconstrictive agents can beadministered prior to injection with the chemodenervating agent orsimultaneously with the chemodenervating agent.

[0008] A composition having a chemodenervating agent, a localanesthetic, and a local vasoconstrictive agent also is featured.

[0009] In another aspect, the invention features an article ofmanufacture that includes packaging material and an amount of achemodenervating agent. The packaging material includes a label thatindicates the chemodenervating agent is useful for treating a patienthaving a wound. Administration of the chemodenervating agent enhanceshealing of the wound. The chemodenervating agent can be a botulinumtoxin such as botulinum toxin A. The article of manufacture also caninclude a local anesthetic agent or a vasconstrictive agent.

[0010] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used topractice the invention, suitable methods and materials are describedbelow. All publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting.

[0011] Other features and advantages of the invention will be apparentfrom the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a graph that indicates the mean differences of thescores of the paired experimental and control scars across threeobservers.

DETAILED DESCRIPTION

[0013] As described herein, the cosmetic appearance of a scar isinfluenced by underlying muscle activity during the wound healingprocess. Paralysis of the underlying muscle activity increases the rateof healing and yields a better cosmetic result. Without being bound by aparticular mechanism, locally induced paralysis of the musculaturesubjacent to a cutaneous defect is thought to minimize the repetitivetensile forces on the wound edges, resulting in superior cosmeticoutcome in the resultant scar.

[0014] Thus, the invention provides a method for treating a patienthaving a wound that includes locally administering an amount of achemodenervating agent effective to enhance wound healing in thepatient. As used herein, “chemodenervating agent” refers to any agentthat interrupts nerve impulse transmission across the neuromuscularjunction, blocks the release of neurotransmitters, or alters the actionpotential at the voltage gated sodium channel of neurons, sufficient toreduce tension within muscles in and near a wound site. As used herein,“wound” refers to skin, tendon, or bone wounds, and can includeinflammatory lesions or other lesions adversely affected by muscletension or movement. Skin wounds include, for example, faciallacerations such as those introduced by trauma (i.e., a car accident),or iatrogenic, such as surgically introduced incisions. In particular,surgically introduced incisions include scar revision excision surgery.As such, a skin wound includes elective incisions and nonelectiveincisions. Skin wounds may be relatively favorable or unfavorable. Asused herein, “favorable wound” refers to an incision or laceration thatis relatively parallel to RSTLs, whereas “unfavorable wound” refers toan incision relatively perpendicular to RSTLs. Both favorable andunfavorable wounds benefit from the methods described herein. Tendonwounds include, for example, ruptured or injured tendons and tendinitis.

[0015] Bone wounds include favorable and unfavorable fractures. A“favorable fracture” refers to a fracture that is not prone todisplacement of one or more fragments of the fracture by muscle pull,whereas an “unfavorable fracture” refers to a fracture that is prone todisplacement of one or more fragments by muscle pull. The treatment fora fracture can be facilitated if muscle tension on the affected fractureis minimized. Thus, the treatment becomes less invasive, less timeconsuming and/or less costly. For example, with a fractured elbow, thetriceps muscle can displace the bone fragments. An alternative tosurgical repair includes use of percutaneous wires to hold the bones inplace, and relaxation of the triceps muscle by paralysis with achemodenervating agent. Use of wires and a chemodenervating agent mayreduce or avoid surgery and/or the accompanying general anesthesia.

[0016] The methods described herein enhance wound healing by minimizingthe adverse effect of muscle tension and movement on the wound, as wellas improving cosmetic appearance through reduced scar development. Inaddition, inflammation may be reduced during the healing process.

Chemodenervating Agents

[0017] Non-limiting examples of chemodenervating agents includebotulinum toxin, saxitoxin, tetanus toxin, and tetrodotoxin. Suitablebotulinum toxins include, for example, botulinum toxins A, B, C (C1 andC2), D, E, F, or G. Botulinum toxins A, B, and F are particularlyuseful. Botulinum toxin A is a potent drug that produces temporarymuscular paralysis when injected locally. Botulinum toxin A has beenused in the treatment of a wide range of disorders associated withinvoluntary muscle contraction. It has been demonstrated to be effectivein treating focal dystonias such as blepharospasm, nondystonic disorderssuch as hemifacial spasms, disorders of conjugate eye movement such asstrabismus and nystagmus, spasticity disorders such as multiplesclerosis and cerebral palsy, and for disorders of localized musclespasm. In addition, botulinum toxin A has been used to treat age relatedrhytids of the upper face. Botulinum toxin A is safe and effective touse, and is relatively painless with rare side effects characterized asmild and transient. Onset of action takes place within 24 to 72 hoursafter injection and lasts 2 to 6 months. Botulinum toxin A is availablecommercially, e.g. from Allergan, Inc. (Irvine, Calif., Botox®) andSpeywood Pharmaceuticals (England, Dysport®).

[0018] Dosages of botulinum toxin A required for local immobilizationtypically do not exceed 1 unit toxin per kg body weight and are safe.Primate studies have indicated that no systemic effects are observed atdosages below 33 units/kg body weight. See, for example, Scott andSuzuki, Mov. Disord., 1988, 3:333-335.

[0019] Botulinum toxins B and F also have been used for dystoniapatients. Greene, P. E. et al., Mov. Disord., 1996, 11(2):181-184; andTruong, D. D. et al., Mov. Disord., 1997, 12(5):772-775. Botulinum toxinB is available from Elan Corporation (Dublin, Ireland, Neurobloc®).

[0020] Botulinum toxins also can be obtained by purifying the toxinsfrom strains of Clostridium botulinum, using standard techniques. Forexample, botulinum toxin A can be produced in a Hall strain using anutritive medium containing casein digest, yeast extract, and dextrose.After lysis of the culture, the toxin is released into the medium andactivated by proteases, and then is acid precipitated. Furtherpurification can include extraction with a sodium phosphate buffer,ethanol precipitation, and crystallization in ammonium sulfate. See, forexample, Schantz, E. J. and Johnson, E. A., Microbiol. Rev., 1992,56(1):80-99.

[0021] Other chemodenervating agents such as saxitoxin, tetanus toxin,and tetrodotoxin are also suitable. The paralysis induced by saxitoxin,however, does not last as long as that induced by botulinum toxin.Consequently, repeated injections of saxitoxin may be needed. Saxitoxincan be purified by known procedures. See, for example, Schantz, E. J. etal., J. Am. Chem. Soc., 1975, 97:1238-1239. Tetanus toxin can decreaseacetylcholine release in cholinergic peripheral nerves when injectedlocally. Dreyer, F., Peripheral actions of tetanus toxin, p. 179-202,In: Botulinum neurotoxin and tetanus toxin. Academic Press, Inc., SanDiego. L. L. Simpson (ed.). Tetanus toxin also can enter the centralnervous system where it causes uncontrolled muscle spasms. When tetanustoxin is employed in the methods described herein, precautions must betaken to ensure local response. Matsuda, M. et al., Biochem. BiophysRes. Commun., 1982, 104:799-805; and Habermann, E. et al.,Naunyn-Schmiedeberg's Arch. Pharmacol., 1980, 311:33-40. Tetanus toxincan be purified by standard procedures. See, for example, Robinson, J.P., Methods Enzymol., 1988, 165:85-90. Tetrodotoxin blocks the sodiumchannel of excitable membranes of nerve and muscle tissues, and can bepurified using routine techniques. See, for example, Yotsu, M. et al.,Toxicon, 1987, 25:225-228.

[0022] Local administration of the chemodenervating agents typicallyoccurs by subcutaneous (SQ), intramuscular (IM), perimuscular injection,or percutaneous instillation (e.g., air gun or skin patch). Whenchemodenervating agents are injected SQ, the agent reaches the muscle byperfusion. For elective incisions, the chemodenervating agent can beadministered prior to making an incision, while making an incision, orafter an incision has been made.

Administration of Local Anesthetics and Local Vasoconstrictive Agents

[0023] The method of treatment further can include administering eithera local anesthetic agent or a local vasoconstrictive agent, or both.Such agents can be administered prior to injection of thechemodenervating agent or simultaneously with the injection of thechemodenervating agent. Local anesthetics block nerve conduction, andcan cause sensory and motor paralysis in a localized area. Localanesthetics have a rapid onset of action, and therefore reduce muscletension on the wound almost immediately as well as reduce painassociated with the injection. The extent of muscular paralysis achievedby a local anesthetic agent is helpful in predicting the extent ofparalysis that can be achieved by subsequent injection of achemodenervating agent into the same injection site. Thus, possiblelocal side effects, such as diffusion of the chemodenervating agent toadjacent muscle groups, is prevented. Non-limiting examples of localanesthetic agents include lidocaine, bupivacaine, chloroporcaineetidocaine, or mepivacaine, and are available commercially. In addition,other amide types of local anesthetics can be used in the method.Suitable amounts of local anesthetics can be readily determined by aphysician. For example, about 1 to 5 mls of lidocaine at a concentrationof about 0.5%-about 2% can be injected. Administration of localanesthetics is particularly useful when incisions are introducedsurgically, such as during scar reversion excision surgery.

[0024] Administration of a local vasoconstrictive agent results in adecreased hemoperfusion of the injected tissue. Thus, administration ofa local vasoconstrictive agent can help prevent or control diffusion ofthe chemodenervating agent and minimize possible side effects, such asbrow ptosis or incomplete eye closure from injection into the frontalisand/or corrugator supercilii muscles. Non-limiting examples of localvasoconstrictive agents include epinephrine and phenylephrine, and areavailable commercially. A suitable amount of a local vasoconstrictiveagent can be readily determined by a physician. For example, 5 mls ofepinephrine 1:100,000 or 1:200,000 typically is used for localvasoconstrictive action.

[0025] Compositions containing a chemodenervating agent and a localanesthetic, and/or a local vasoconstrictive agent, can be produced forapplications in which it is desired to introduce chemodenervating agentsand one or more other components simultaneously. Such compositions canbe prepared, for example, by reconstituting a lyophilized component witha solution of another component. For example, lyophilized botulinumtoxin can be reconstituted in a solution containing a local anestheticand a local vasoconstrictive agent, or in a solution containing either alocal anesthetic or a local vasoconstrictive agent. A compositioncontaining lidocaine and epinephrine is commercially available, forexample, from Astra. Typically, lidocaine is present at 0.5-2% andepinephrine is present at 1:100,000 to 1:200,000.

[0026] The invention will be further described in the followingexamples, which do not limit the scope of the invention described in theclaims.

EXAMPLE 1 Enhanced Wound Healing By Injection of a ChemodenervatingAgent in Monkeys

[0027] In order to closely mimic the effects of muscle activity on humanfacial skin wounds, the use of an appropriate animal model wasmandatory. Due to extensive skin laxity and inadequate mimeticmusculature, established models like rats, pigs, and horses, were notideal for this purpose. Cynomolgus macaque monkeys (Macaca fascicularis)were chosen as a model since the anatomy of their cranio facial andcutaneous anatomy resembles that of humans.

[0028] The study was approved by the Institutional Committee of AnimalCare and Use at the Mayo Clinic and the animals were housed, cared for,and fed in compliance with the institutional guidelines. No animal wassacrificed. All procedures were performed with anesthesia consisting ofKetamine at 20 mg/kg IM (Ketaset®, Fort Dodge), Xylazine at 0.5 mg/kg IM(Rompun®, Bayer), and Isoflurane at 1% (Isoflurane®, Abbott).

[0029] The forehead was chosen for the excision site in the monkeys asthe frontalis, procerus and corrugator supercilii muscles constantlyexert tension on the forehead skin and paralysis of these muscles leadsto no functional deficit. In order to minimize local variables, theexperimental and control excisions were each planned in symmetricanatomic location in the same individual animal. Three Y-shapedexcisions with their main axis perpendicular to the RSTLs were plannedsymmetrically in relation to the midline on each side of the forehead.

[0030] A template was used to determine the location and outline of theexcisions to ensure maximal precision. An experienced facial plasticsurgeon, blinded to the experimental conditions, performed allexcisions. Using standard surgical technique, the skin and subcutaneoustissue was excised and the frontalis muscle was preserved in the base ofthe defects. Subsequently, one side of the forehead was randomlydetermined as experimental and the mimetic musculature adjacent to eachexcision on that side was injected under direct vision with 7 units ofBotulinum Toxin A (Botox ®, Allergan) in 0.9% saline (25 units/ml),resulting in a total dose of 21 units of Botulinum toxin A per halfforehead. The control side was injected in the same fashion with anequal volume of 0.9% saline alone. All wounds were closed with a single6-0 Chromic Gut (Chromic Gut®, Ethicon) buried suture and multiple 5-0black monofilament Nylon (Ethilon®, Ethicon) superficial sutures. Fromthe third day postoperatively, marked paralysis of the Botulinum toxin Atreated side was observed in all six animals. Extraocular musclemovement and eyelid closure were not compromised.

[0031] Three experienced facial surgeons, who were not present duringthe surgical procedures, were used as blinded observers to evaluate thecosmetic appearance of the scars at 1, 4, and 12 weeks postoperatively.Care was taken to sedate the animals deeply for each assessment so theevaluators were not able to recognize the paralyzed side of theforehead.

[0032] First, the evaluators were asked to score each single scar on a10 cm visual analogue scale. The 36 forehead scars (3 experimental scarsand 3 control scars per animal) were evaluated by each assessorindependently. In this scale, scars were rated from 1 to 10, with 0being the worst and 10 being the best. At 1 and 4 weeks postoperatively,none of the blinded ratings revealed a significantly better cosmeticappearance of the experimental or the control wounds. The mean ratingsof the three assessors at 12 weeks postoperatively reached a higherscore on the experimental side in 16 of 18 of the symmetric pairs ofscars (FIG. 1). The bars in FIG. 1 represent the mean differences of thescores of the paired experimental and control scars across the threeobservers. The mean score by assessor #1 was 9.4 for the experimentalscars and 8.1 for the control scars; the mean score by assessor #2 was8.0 for the experimental scars and 7.3 for the control scars; and themean score by assessor #3 was 7.9 for the experimental scars and 7.3 forthe control scars. The mean scores across the three assessors were 8.4(SD 1.0) for the experimental side and 7.6 (SD 0.9) for the controlside. The statistical assessment of an intervention effect was based onusing the average rating across the three evaluators and fitting atwo-factor (intervention, site) repeated measures analysis of variancemodel, taking into account the correlation of measurements obtained onthe same animal. Based on this analysis, the scars on the experimentalside were rated significantly better than the scars on the control side(p<0.01).

[0033] Secondly, the assessors were asked to examine the groups of 3scars on either side of each animal's forehead (12 weekspostoperatively) and to rate each scar as better, equal to, or worsethan its symmetric counterpart. A consensus score was derived from themajority of the votes. The experimental sides were assessed as betterthan the control sides in 6 of the 6 animals. Based on a two-tailed,one-sample binomial test, this result was statistically significant(p<0.031) (Table 1). TABLE 1 Assessment of Scars Consensus AnimalAssessor 1 Assessor 2 Assessor 3 Score 1 + ? + + 2 + ? + + 3 + + − +4 + + + + 5 + + + + 6 + + + +

[0034] Representative sections of the scars were excised 12 weekspostoperatively, using a 4 mm punch. The biopsy specimens were embeddedin formalin, cut in 25 μm thick sections, and hematoxylin and Eosinstained for evaluation. Scars were classified as mature with no sign ofinflammation or ongoing remodeling.

EXAMPLE 2 Enhanced Wound Healing By Botulinum Toxin A Injection InHumans

[0035] A male patient (26 years of age, 82 kg) underwent scar revisionexcision surgery. The scar was located on the forehead approximately 2cm lateral of the midline on the left, and approximately 3 cm cranial tothe most superior extension of the orbital rim. Its direction washorizontal, giving it a favorable position relative to the wrinklelines. The scar was a result of a trauma at age seven, and was closed ata tertiary referral center at the time.

[0036] The patient was placed in a supine position, and 5 ml of 0.5%lidocaine with 1:200,000 epinephrine was locally injected. The scar wasexcised and bleeding was controlled with monopolar cautery. Botulinumtoxin A was injected (10 units) into the frontalis muscle under directvision fanning out from the wound. The wound was closed using 6-0 Vicrylfor deep and 6-0 Nylon for superficial sutures. An additional 7.5 unitsof botulinum toxin A were injected into the procerus and corrugatormuscles bilaterally, as frowning caused distortion of the wound.

[0037] Approximately 24 hours after surgery, the patient developedmarked paralysis of the injection muscles, and had lost the ability towrinkle the forehead skin in an area of about 4 cm in diameter aroundthe excision. The wound healed well in the early postoperative period.It was apparent that there was decreased movement and tension on thewound edges. The forehead wound of the patient healed withoutcomplications. Compared to the preoperative scar, the cosmeticappearance of the resulting scar 12 months postoperatively was excellentand superior to the initial scar.

EXAMPLE 3 Evaluation of Scars From Patients Infected With aChemodenervating Agent Alone or in Combination With a Local Anesthetic

[0038] Healthy volunteers were informed about potential risks and sideeffects of the treatment. Formal written informed consent was obtainedin accordance with the Mayo Institutional Review Board regulations.Prior to enrollment in the study, symmetry of frontalis, procerus, andcorrugator supercilii function was assessed and subjects were onlyincluded in the study if there was no functional asymmetry present. Theforehead of the subjects was divided by the midline into two symmetricsides, one serving as the control and the other as the experiment side.The side of the forehead which was to serve as control was determinedrandomly, and was injected with Botulinum Toxin A (Botox) reconstitutedin 0.9% saline. The experimental side was injected with Botulinum ToxinA reconstituted in 1% or 2% lidocaine with 1:100,000 epinephrine. Thecombination of these agents with Botulinum toxin A was achieved byreconstituting 100 units of freeze dried Botulinum toxin A in 5 ml of 1%or 2% Lidocaine with 1:100,000 epinephrine solution (Xylocaine at 1% or2% with epinephrine 1:100,000, Astra). This resulted in a dosage whichis commonly utilized for each of these substances in routine clinicaluse (20 units Botulinum toxin per ml of 1% or 2% lidocaine with1:100,000 epinephrine).

[0039] In order to assure symmetry and equality of the injections, thesites of injection were predetermined with a template. A predeterminedamount and volume of toxin was injected into each location. After theinjection, subjects were asked to evaluate the intensity of the painresulting from the percutaneous injections for both sides of theforehead separately. This was done with a standardized questionnaireapproximately 10 minutes after the injection. The pattern of muscularparalysis achieved by the local anesthetic plus Botox was compared tothe pattern of paralysis resulting from Botox A alone at one week afterthe injection. The potency and duration of action of Botox Areconstituted in the vasoconstrictive and anesthetic agent was comparedto Botox A reconstituted in 0.9% saline by serial observation until thereturn of facial muscular function. Subjects were photographed 5-15minutes after injection, one week after injection, and monthlythereafter attempting maximal forehead muscle contracture.

[0040] Two particular examples of such injections are provided. A whitefemale was injected with 20 units Botox in 1 ml 1% lidocaine with1:100,000 epinephrine in the right side of the forehead and in exactlythe same fashion with 20 units Botox, reconstituted in 0.9% saline inthe left side of the forehead. A second white female was injected in thesame manner, except that 2% lidocaine was used. Eight portions of 0.125ml were injected into each side of the forehead and the sites ofinjection were determined by a template. Each subject immediatelydeveloped paralysis of the frontalis, procerus, and depressor superciliimuscles on the right side of the forehead. The pattern and extent ofimmediate muscular paralysis resulting from the immediate action of thelocal anesthetic drug (Lidocaine 1% or 2%) was predictable of thepattern and extent of delayed paralysis achieved by Botox one weeklater. The effect of the Botox-induced muscular paralysis faded in asymmetric fashion, indicating that the duration of Botox inducedmuscular paralysis was not affected by the addition of Lidocaine orepinephrine.

Other Embodiments

[0041] It is to be understood that while the invention has beendescribed in conjunction with the detailed description thereof, theforegoing description is intended to illustrate and not limit the scopeof the invention, which is defined by the scope of the appended claims.Other aspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method for treating a patient having a wound,said method comprising locally administering an amount of achemodenervating agent such that healing of said wound is enhanced. 2.The method of claim 1, wherein said chemodenervating agent is abotulinum toxin.
 3. The method of claim 1, wherein said botulinum toxinis selected from the group consisting of botulinum toxin A, B, C, D, E,F, and G.
 4. The method of claim 3, wherein said botulinum toxin isbotulinum toxin A.
 5. The method of claim 3, wherein said botulinumtoxin is botulinum toxin B.
 6. The method of claim 1, wherein saidchemodenervating agent is saxitoxin.
 7. The method of claim 1, whereinsaid chemodenervating agent is tetanus toxin.
 8. The method of claim 1,wherein said chemodenervating agent is tetrodotoxin.
 9. The method ofclaim 1, wherein said administering step is by injection.
 10. The methodof claim 9, wherein said chemodenervating agent is subcutaneouslyinjected.
 11. The method of claim 9, wherein said chemodenervating agentis intramuscularly injected.
 12. The method of claim 9, wherein saidchemodenervating agent is percutaneously instilled.
 13. The method ofclaim 1, said method further comprising administering a localanesthetic.
 14. The method of claim 13, wherein said local anesthetic islidocaine.
 15. The method of claim 13, wherein said local anesthetic isbupivacaine.
 16. The method of claim 13, wherein said local anestheticis mepivacaine.
 17. The method of claim 13, wherein said localanesthetic is administered prior to administration of saidchemodenervating agent.
 18. The method of claim 1, said method furthercomprising administering a local vasoconstrictive agent.
 19. The methodof claim 18, wherein said local vasoconstrictive agent is epinephrine.20. The method of claim 1, said method further comprising administeringa local anesthetic and a vasoconstrictive agent.
 21. The method of claim20, wherein said local anesthetic and said vasoconstrictive agent areadministered prior to said chemodenervating agent.
 22. The method ofclaim 1, wherein said wound is a facial wound.
 23. A compositioncomprising a chemodenervating agent, a local anesthetic agent, and avasoconstrictive agent.
 24. The composition of claim 23, wherein saidchemodenervating agent is botulinum toxin.
 25. An article of manufacturecomprising packaging material and an amount of a chemodenervating agent,wherein said packaging material comprises a label that indicates saidchemodenervating agent is useful for treating a patient having a wound,and wherein local administration of said amount of said chemodenervatingagent enhances healing of said wound.
 26. The article of manufacture ofclaim 25, wherein said chemodenervating agent is a botulinum toxin. 27.The article of manufacture of claim 25, wherein said botulinum toxin isbotulinum toxin A.
 28. The article of manufacture of claim 25, whereinsaid botulinum toxin is botulinum toxin B.
 29. The article ofmanufacture of claim 25, said article of manufacturing furthercomprising a local anesthetic.
 30. The article of manufacture of claim25, said article of manufacture further comprising a localvasoconstrictive agent.
 31. The article of manufacture of claim 25, saidarticle of manufacture further comprising a local anesthetic and a localvasoconstrictive agent.